title: Metabolic regulation of cancer cell side population by glucose through activation of the Akt pathway.
abstract: Side population (SP) cells within tumors are a small fraction of cancer cells with stem-like properties that can be identified by flow cytometry analysis based on their high ability to export certain compounds such as Hoechst 33342 and chemotherapeutic agents. The existence of stem-like SP cells in tumors is considered as a key factor contributing to drug resistance, and presents a major challenge in cancer treatment. Although it has been recognized for some time that tumor tissue niches may significantly affect cancer stem cells (CSCs), the role of key nutrients such as glucose in the microenvironment in affecting stem-like cancer cells and their metabolism largely remains elusive. Here we report that SP cells isolated from human cancer cells exhibit higher glycolytic activity compared to non-SP cells. Glucose in the culture environment exerts a profound effect on SP cells as evidenced by its ability to induce a significant increase in the percentage of SP cells in the overall cancer cell population, and glucose starvation causes a rapid depletion of SP cells. Mechanistically, glucose upregulates the SP fraction through ATP-mediated suppression of AMPK and activation of the Akt pathway, leading to elevated expression of the ATP-dependent efflux pump ABCG2. Importantly, inhibition of glycolysis by 3-BrOP significantly reduces SP cells in vitro and impairs their ability to form tumors in vivo. Our data suggest that glucose is an essential regulator of SP cells mediated by the Akt pathway, and targeting glycolysis may eliminate the drug-resistant SP cells with potentially significant benefits in cancer treatment.
authors.affiliation: 1] State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China [2] Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: P-P
authors.initials: PP
authors.lastname: Liu
authors.forename: J
authors.initials: J
authors.lastname: Liao
authors.forename: Z-J
authors.initials: ZJ
authors.lastname: Tang
authors.forename: W-J
authors.initials: WJ
authors.lastname: Wu
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.forename: Z-L
authors.initials: ZL
authors.lastname: Zeng
authors.forename: Y
authors.initials: Y
authors.lastname: Hu
authors.forename: P
authors.initials: P
authors.lastname: Wang
authors.forename: H-Q
authors.initials: HQ
authors.lastname: Ju
authors.forename: R-H
authors.initials: RH
authors.lastname: Xu
authors.forename: P
authors.initials: P
authors.lastname: Huang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D006842:Hydrocarbons, Brominated / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011422:Propionates / Q000494:pharmacology / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects*; D014183:Transplantation, Heterologous
chemical_list: C568307:3-bromo-2-oxopropionate-1-propyl ester; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D002867:Chromones; D006842:Hydrocarbons, Brominated; D009025:Morpholines; D009363:Neoplasm Proteins; D011422:Propionates; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases; D005947:Glucose